Aquaporin 2-labeled cells differentiate to intercalated cells in response to potassium depletion

The mammalian renal collecting duct consists of principal cells (PCs) and intercalated cells (ICs). Both PCs and ICs are involved in potassium (K⁺) homeostasis, PCs through their role in K⁺ secretion and ICs through their ability to facilitate K⁺ resorption. We previously hypothesized that PCs may differentiate into ICs upon K⁺ depletion. However, no direct evidence has yet been obtained to conclusively demonstrate that PCs differentiate into ICs in response to K⁺ depletion. Here, we present direct evidence for the differentiation of PCs into ICs by cell lineage tracing using aquaporin 2 (AQP2)-Cre mice and R26R-EYFP transgenic mice. In control mice, AQP2-EYFP⁺ cells exhibited mainly a PC phenotype (AQP2-positive/H⁺-ATPase-negative). Interestingly, some AQP2-EYFP⁺ cells exhibited an IC phenotype (H⁺-ATPase-positive/AQP2-negative); these cells accounted for 1.7 %. After K⁺ depletion, the proportion of AQP2-EYFP⁺ cells with an IC phenotype was increased to 4.1 %. Furthermore, some AQP2-EYFP⁺ cells exhibited a “null cell” phenotype (AQP2-negative/H⁺-ATPase-negative) after K⁺ depletion. Collectively, our data demonstrate that AQP2-labeled cells can differentiate into ICs, as well as null cells, in response to K⁺ depletion. This finding indicates that some of AQP2-labeled cells possess properties of progenitor cells and that they can differentiate into ICs in the adult mouse kidney.